2-aryl-propionic acids and pharmaceutical compositions containing them

ABSTRACT

(R) and (S) 2-Aryl-propionic acids, and pharmaceutical compositions that contain them, are useful in inhibiting chemotactic activation of neutrophils (PMN leukocytes) induced by the interaction of Interleukin-8 (IL-8) with CXCR1 and CXCR2 membrane receptors. The acids are used for the prevention and treatment of pathologies deriving from said activation. In particular, the (R) enantiomers of said acids are lacking cyclo-oxygenase inhibition activity and are particularly useful in the treatment of neutrofil-dependent pathologies such as psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bollous pemphigo, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.

This application is the National Stage of International Applicationnumber PCT/EP2002/012939 filed Nov. 19, 2002, which claims priorityunder 35 USC §119(a)-(d) of Application No. MI2001A002434 filed in Italyon Nov. 20, 2001.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to (R,S) 2-aryl-propionic acids, theirsingle enantiomers (R) and (S) and to pharmaceutical compositionscontaining them, which are used in the prevention and treatment oftissue damage due to the exacerbated recruitment of polymorphonucleatedneutrophils (PMN leukocytes) at inflammation sites.

STATE OF THE ART

Particular blood cells (macrophages, granulocytes, neutrophils,polymorphonucleated) respond to a chemical stimulus (when stimulated bysubstances called chemokines) by migrating along the concentrationgradient of the stimulating agent, through a process called chemotaxis.The main known stimulating agents or chemokines are represented by thebreakdown products of complement C5a, some N-formyl peptides generatedfrom lysis of the bacterial surface or peptides of synthetic origin,such as formyl-methionyl-leucyl-phenylalanine (f-MLP) and mainly by avariety of cytokines, including Interleukin-8 (IL-8). Interleukin-8 isan endogenous chemotactic factor produced by most nucleated cells suchas fibroblasts, macrophages, endothelial and epithelial cells subjectedto the TNF-α (Tumor Necrosis Factor) stimulus, interleukins IL-1 α andIL-1 β and bacterial wall lipopolysaccharides (LPS), as well as the sameneutrophils exposed to the action of LPS or N-formyl peptides ofbacterial origin (f-MLP). Belonging to the family of this chemotacticfactor [also known as neutrophil activating factor (NAF), T-lymphocytechemotactic factor, monocyte derived neutrophils chemotactic factor(MDNCF)] is a series of IL-8-like chemokines [GRO α, β, γ and NAP-2],which bind to the IL-8 receptors (Chang et al., J. Immunol., 148, 451,1992). Neutrophils are the first line of defense against bacterialinfection, owing to the ability of these cells to migrate from theperipheral blood through the endothelial junctions and the tissuematrices towards the action sites (i.e. along chemotactic factorconcentration gradients) where they act by attacking the microorganisms,removing damaged cells and repairing tissues (M. A. Goucerot-Podicalo etal., Pathol. Biol (Paris), 44, 36, 1996).

In some pathological conditions, marked by exacerbated recruitment ofneutrophils, a more severe tissue damage at the site is associated withthe infiltration of neutrophilic cells. Recently, the role ofneutrophilic activation in the determination of damage associated withpost ischemia reperfusion and pulmonary hyperoxia was widelydemonstrated. Experimental models [N. Sekido et al., Nature, 365, 654,1993 and T. Matsumoto et al., Lab. Investig., 77, 119, 1997] andclinical studies [A Mazzone et al., Recent Prog. Med., 85, 397, 1994; G.Receipts et al., Atheroscl., 91, 1, 1991] have shown the directcorrelation between cellular damage and the extent of PMN leukocyteinfiltration, 18 being the most specific and powerful activator thereof.In patients affected by acute respiratory insufficiency (ARDS), theexacerbated recruitment of neutrophils in the airways and in pulmonaryfluids can be closely correlated with the concentration of the cytokineIL-8 (E. J. Miller et al., Am. Rev. Respir. Dis., 146, 437, 1992) andwith the severity of the pathology (Kurodowska et al., Immunol., 157,2699, 1996). Treatment with anti-IL-8 antibody was shown to be effectivein models of acute respiratory insufficiency and pulmonary damage causedby endotoxemia (K. Yokoi et al.; Lab. invest., 76, 375, 1997).

The specific role of IL-8 in causing damage following post ischemiareperfusion in patients affected by acute myocardium infarction wasshown (Y. Abe et al., Br. Heart J., 70, 132, 1993); the key role exertedby IL-8 in the mediation of the damage associated with the post ischemiareperfusion is corroborated also by the results obtained using theanti-IL-8 antibody in an experimental model of focal cerebral ischemiain rabbits (T. Matsumoto et al., Lab. invest., 77, 119, 1997).

The biological activity of IL-8 is mediated by the interaction of theinterleukin with CXCR1 and CXCR2 membrane receptors which belong to thefamily of seven transmembrane receptors, expressed on the surface ofhuman neutrophils and of certain types of T-cells (L. Xu et al., J.Leukocyte Biol., 57, 335, 1995).

Although CXCR1 activation is known to play a crucial role inIL-8-mediated chemotaxis, it has been recently supposed that CXCR2activation could play a pathophysiological role in cronic inflammatorydiseases such as psoriasis. In fact, the pathophysiological role of IL-8in psoriasis is also supported by the effects of IL-8 on keratinocytefunctions. Indeed, IL-8 has been shown to be a potent stimulator ofepidermal cell proliferation as well as angiogenesis, both importantaspects of psoriatic pathogenesis (A. Tuschil et al. J Invest Dermatol,99, 294, 1992; Koch A E et al, Science, 258, 1798, 1992). Additionally,IL-8 induced the expression of the major histocompatibility complex II(MHC-II) moiety HLA-DR on cultured keratinocytes (L. Kemeny et al., IntArch Allergy Immunol, 10, 351, 1995). The effect of CXCL8 onkeratinocyte function is supposed to be mediated by CXCR2 activation. Inagreement with this hypothesis, it was reported that CXCR2 isoverexpressed in epidermal lesional skin of psoriatic patients (R. Kulkeet al., J. Invest. Dermatol., 110, 90, 1998).

In addition, there is accumulating evidence that the pathophysiologicalrole of IL 8 in melanoma progression and metastasis could be mediated byCXCR2 activation.

The potential pathogenetic role of IL-8 in cutaneous melanoma isindependent on its chemotactic activity on human PMNs. In fact, IL-8 issupposed to act as an autocrine growth and metastatic factor formelanoma cells.

Consistent amount of CXL8 have been found to be produced by melanomacells and melanoma tumor cells are known to express immuneractive CXCR2receptor (L. R. Bryan et al., Am J Surg, 174, 507, 1997). IL-8 is knownto induce haptotactic migration as well as proliferation of melanomacells (J. M. Wang et al., Biochem Biophys Res Commun, 169, 165, 1990).

Potential pathogenic role of IL-8 in pulmonary deseases (lung injury,acute respiratory distress syndrome, asthma, chronic lung inflammation,and cystic fibrosis) and, specifically, in the pathogenesis of COPD(chronic obstructive pulmonary disease) through the CXCR2 receptorpathway has been widely described (D. W P Hay and H. M. Sarau., CurrentOpinion in Pharmacology 2001, 1:242-247).

Phenylureido compounds have been described, which can selectivelyantagonize the binding of IL-8 to the CXCR2 receptor (J. R. White etal., J. Biol. Chem., 273, 10095, 1998); the use of these compounds inthe treatment of pathological states mediated by Interleukin-8 isclaimed in WO 98/07418.

Studies on the contribution of single (S) and (R) enantiomers ofketoprofen to the anti-inflammatory activity of the racemate and ontheir role in the modulation of the chemokine have demonstrated (P.Ghezzi et al., J. Exp. Pharm. Ther., 287, 969, 1998) that the twoenantiomers and their salts with chiral and non-chiral organic bases caninhibit in a dose-dependent way the chemotaxis and increase inintracellular concentration of Ca²⁺ ions induced by IL-8 on human PMNleukocytes (U.S. Pat. No. 6,069,172). It has been subsequentlydemonstrated (C. Bizzarri et al., Biochem. Pharmacol. 61, 1429, 2001)that Ketoprofen shares the inhibition activity of the biologicalactivity of IL-8 with other molecules belonging to the class ofnon-steroidal anti-inflammatory (NSAIDs) such as flurbiprofen, ibuprofenand indomethacin. The cyclo-oxygenase enzyme (COX) inhibition activitytypical of NSAIDs limits the therapeutical application of thesecompounds in the context of the treatment of neutrophil-dependentpathological states and inflammatory conditions such as psoriasis,idiopathic pulmonary fibrosis, acute respiratory failure, damages fromreperfusion and glomerulonephritis. The inhibition of prostaglandinsynthesis deriving from the action on cyclo-oxygenase enzymes involvesthe increase of the cytokine production which, like TNF-α, play a rolein amplifying the undesired pro-inflammatory effects of neutrophils.

The lower COX inhibitory potency of the (R) enantiomers of NSAIDsbelonging to the subclass of phenylpropionic acids, compared to thepotency of the (S) enantiomers, has suggested that the (R) enantiomersof ketoprofen, flurbiprofen and ibuprofen might be potentially usefulagents in the therapy of neutrophil-dependent pathologies. The fact thatsome (R) enantiomers are converted in vivo into the corresponding (S)enantiomers in several animals species and in humans, thus recoveringCOX inhibitory activity, is a severe limit to the use of these compoundsin the therapy of IL-8 mediated pathologies.

The outlined premises account for the hard difficulties which have beenmet so far in the identification of selective IL-8 inhibitors belongingto the class of 2-phenylpropionic acids. It has been proposed thatchiral inversion of R enantiomers of 2-phenylpropionic acids is due tothe stereospecific formation of the intermediates R-profenyl-CoAthioesters; it has been demostrated hence that the carboxylic functionderivatisation allows to avoid the “in vivo” metabolic inversion withoutaffecting the IL-8 inhibition efficacy.

Structure Activity Relationship studies performed in the class of2-phenylpropionic acid derivatives led to the identification of novelclasses of potent and selective inhibitors of IL-8 biological activitiessuitable for “in vivo” administration. R-2-arylpropionic acid amides andN-acylsulfonamides have been described as effective inhibitors of IL-8induced neutrophils chemotaxis and degranulation (WO 01/58852; WO00/24710).

DETAILED DESCRIPTION OF THE INVENTION

We have now found out that selected subclasses of 2-aryl-propionic acidsshow the surprising ability to effectively inhibit IL-8 inducedneutrophils chemotaxis and degranulation without any evident effect onthe cyclooxygenases activity.

Both the R and the S enantiomer of the (R,S)-2-aryl-propionic acidsdescribed herebelow are in fact inactive in the inhibition ofcyclooxygenases in a concentration range between 10⁻⁵ and 10⁻⁶ M.

The present invention thus provides (R,S)-2-aryl-propionic acids offormula (I) and their single (R) and (S) enantiomers:

and pharmaceutically acceptable salts thereof,wherein

-   Ar is a phenyl ring substituted by    -   a group in the 3 (meta) position selected from a linear or        branched C₁-C₅ alkyl, C₂-C₅-alkenyl or C₂-C₅-alkynyl group        optionally substituted by C₁-C₅-alkoxycarbonyl, substituted or        not-substituted phenyl, linear or branched C₁-C₅ hydroxyalkyl,        aryl-hydroxymethyl, or the 3 (meta) linear or branched C₁-C₅        alkyl group forms, together with a substituent in ortho or para        position and the benzene ring, saturated or unsaturated,        substituted or non-substituted bicyclo aryls; or    -   a group in the 4 (para) position selected from C₁-C₅-acyloxy,        substituted or not-substituted benzoyloxy, C₁-C₅-acylamino,        substituted or not-substituted benzoylamino, C₁-C₅-sulfonyloxy,        substituted or not-substituted benzenesulfonyloxy,        C₁-C₅-alkanesulfonylamino, substituted or not-substituted        benzenesulfonylamino, C₁-C₅-alkanesulfonylmethyl, substituted or        not-substituted benzenesulfonylmethyl, C₃-C₆-cycloalkyl;        2-furyl; 3-tetrahydrofuryl; 2 thiophenyl; 2-tetrahydrothiophenyl        groups or a C₁-C₈ (alkanoyl, cycloalkanoyl,        arylalkanoyl)-C₁-C₅-alkylamino, e.g. acetyl-N-methyl-amino,        pivaloyl-N-ethyl-amino group; or    -   a group in the 2 (ortho) position selected from substituted or        not substituted arylmethyl, substituted or not substituted        aryloxy, substituted or not substituted arylamino, wherein the        substituents of the aryl group are selected from C₁-C₄ alkyl,        C₁-C₄-alkoxy, chlorine, fluorine and/or trifluoromethyl groups;        for use as inhibitors of IL-8 induced human PMNs chemotaxis.

The phenyl ring in the Ar group may be optionally substituted withfurther groups such as C₁-C₅-alkyl or a halogen group.

The term “substituted” in the above definition means substituted with agroup selected from C₁-C₅-alkyl, halogen, hydroxy, C₁-C₅-alkoxy, amino,C₁-C₅-alkylamino, nitro, or a cyano group.

Preferred Ar in compounds of formula (I) are phenyl groups 3-substitutedby: isoprop-1-en-1-yl, ethyl, isopropyl, pent-2-en-3-yl, pent-3-yl,1-phenyl-ethylen-1-yl, α-methylbenzyl, α-hydroxybenzyl, α-hydroxyethyl,α-hydroxypropyl, bicyclic aryl structures such as 3-methyl-indan-5-yl,3-methyl-indan-7-yl, 8-methyl-tetrahydronaphth-2-yl,5-methyl-tetrahydronaphth-1-yl, and phenyl groups 4-substituted bytrifluoromethanesulfonyloxy, 2-propanesulfonyloxy, benzylsulfonyloxy,benzenesulfonyloxy, 2′-ethylbenzenesulfonyloxy,2′-chlorobenzenesulfonyloxy, methanesulfonylamino,trifluoromethanesulfonylamino, 2-propanesulfonylamino,benzylsulfonylamino, benzenesulfonylamino, 2′-ethylbenzenesulfonylamino,aminosulfonylmethyl, 2′-chlorobenzenesulfonylamino,trifluoromethanesulfonylmethyl, benzenesulfonylmethyl, aminosulfonyloxy,aminosulfonylamino; and phenyl groups 2-substituted by2-(2,6-dichloro-phenylamino)-phenyl,2-(2,6-dichloro-phenyl-amino)-5-chloro-phenyl,2-(2,6-dichloro-3-methyl-phenyl-amino)-phenyl,2-(3-trifluoromethyl-phenyl-amino)-phenyl,2-(2,6-dichloro-phenoxy)-phenyl, 2-(2-chloro-phenoxy)-phenyl,2-(2,6-dichloro-benzyl)-phenyl, 2-(2-chloro-benzyl)-phenyl.

Particularly preferred Compounds of the invention are:

-   (R,S) 2-[3′-(alpha-ethyl-propyl)phenyl]propionic acid-   (R) 2-[3′-(alpha-ethyl-propyl)phenyl]propionic acid-   (S) 2-[3′-(alpha-ethyl-propyl)phenyl]propionic acid-   2-[3′-(alpha-hydroxy-ethyl)phenyl]propionic acid, and the single    diastereoisomers thereof-   2-[3′-(alpha-hydroxy-propyl)phenyl]propionic acid and the single    diastereoisomers thereof-   (R,S) 2-[3′-isopropylphenyl]propionic acid-   (R) 2-[3′-isopropylphenyl]propionic acid-   (S) 2-[3′-isopropylphenyl]propionic acid-   (R) 2-(4′-trifluoromethanesulfonyloxy)phenylpropionic acid-   (S) 2-(4′-trifluoromethanesulfonyloxy)phenylpropionic acid-   (R) 2-(4′-benzenesulfonyloxy)phenylpropionic acid-   (S) 2-(4′-benzenesulfonyloxy)phenylpropionic acid-   (R) 2-[4′-(2″-ethyl)benzenesulfonyloxy]phenylpropionic acid-   (S) 2-[4′-(2″-ethyl)benzenesulfonyloxy]phenylpropionic acid-   (R) 2-[4′-(2″-chloro)phenylsulfonyloxy]phenylpropionic acid-   (S) 2-[4′(2″-chloro)phenylsulfonyloxy]phenylpropionic acid-   (R) 2-[4′-(2″-propane)sulfonyloxy]phenylpropionic acid-   (S) 2-[4′-(2″-propane)sulfonyloxy]phenylpropionic acid-   (R) 2-(4′-benzylsulfonyloxy)phenylpropionic acid-   (S) 2-(4′-benzylsulfonyloxy)phenylpropionic acid-   (R) 2-(4′-aminosulfonyloxy)phenylpropionic acid-   (S) 2-(4′-aminosulfonyloxy)phenylpropionic acid-   (R) 2-(4′-trifluoromethanesulfonylamino)phenylpropionic acid-   (S) 2-(4′-trifluoromethanesulfonylamino)phenylpropionic acid-   (R) 2-(4′-methanesulfonylamino)phenylpropionic acid-   (S) 2-(4′-methanesulfonylamino)phenylpropionic acid-   (R) 2-[4′-(2″-propane)sulfonylamino]phenylpropionic acid-   (S) 2-[4′-(2″-propane)sulfonylamino]phenylpropionic acid-   (R) 2-(4′-benzenesulfonylamino)phenylpropionic acid-   (S) 2-(4′-benzenesulfonylamino)phenylpropionic acid-   (R) 2-[4′-(2″-ethyl)benzenesulfonylamino]phenylpropionic acid-   (S) 2-[4′-(2″-ethyl)benzenesulfonylamino]phenylpropionic acid-   (R) 2-[4′-(2″-chloro)benzenesulfonylamino]phenylpropionic acid-   (S) 2-[4′-(2″-chloro)benzenesulfonylamino]phenylpropionic acid-   (R) 2-(4′-benzylsulfonylamino)phenylpropionic acid-   (S) 2-(4′-benzylsulfonylamino)phenylpropionic acid-   (R) 2-(4′-aminosulfonylamino)phenylpropionic acid-   (S) 2-(4′-aminosulfonylamino)phenylpropionic acid-   (R) 2-(4′-trifluoromethanesulfonylmethyl)phenylpropionic acid-   (S) 2-(4′-trifluoromethanesulfonylmethyl)phenylpropionic acid-   (R) 2-(4′-benzenesulfonylmethyl)phenylpropionic acid-   (S) 2-(4′-benzenesulfonylmethyl)phenylpropionic acid

It is a further object of the present invention to provide novelcompounds of formula (Ia)

their single (R) and (S) enantiomers and pharmaceutically acceptablesalts thereof,

-   -   wherein Ar is a phenyl ring substituted in the 4 (para) position        with a group selected from C₁-C₅-sulfonyloxy, substituted or        not-substituted benzenesulfonyloxy, C₁-C₅-alkanesulfonylamino,        substituted or not-substituted benzenesulfonylamino,        C₁-C₅-alkanesulfonylmethyl, substituted or not-substituted        benzenesulfonylmethyl.

The phenyl ring in the Ar group of formula (Ia) may be optionallysubstituted with further groups such as C₁-C₅-alkyl or a halogen group.

The term “substituted” in the above definition means substituted with agroup selected from C₁-C₅-alkyl, halogen, hydroxy, C₁-C₅-alkoxy, amino,C₁-C₅-alkylamino, nitro, or a cyano group.

Particularly preferred Compounds of Formula Ia as hereinbefore definedare:

-   (R) 2-(4′-trifluoromethanesulfonyloxy)phenylpropionic acid-   (S) 2-(4′-trifluoromethanesulfonyloxy)phenylpropionic acid-   (R) 2-(4′-benzenesulfonyloxy)phenylpropionic acid-   (S) 2-(4′-benzenesulfonyloxy)phenylpropionic acid-   (R) 2-[4′-(2″-ethyl)benzenesulfonyloxy]phenylpropionic acid-   (S) 2-[4′-(2″-ethyl)benzenesulfonyloxy]phenylpropionic acid-   (R) 2-[4′-(2″-chloro)phenylsulfonyloxy]phenylpropionic acid-   (S) 2-[4′(2″-chloro)phenylsulfonyloxy]phenylpropionic acid-   (R) 2-[4′-(2″-propane)sulfonyloxy]phenylpropionic acid-   (S) 2-[4′-(2″-propane)sulfonyloxy]phenylpropionic acid-   (R) 2-(4′-benzylsulfonyloxy)phenylpropionic acid-   (S) 2-(4′-benzylsulfonyloxy)phenylpropionic acid-   (R) 2-(4′-aminosulfonyloxy)phenylpropionic acid-   (S) 2-(4′-aminosulfonyloxy)phenylpropionic acid-   (R) 2-(4′-trifluoromethanesulfonylamino)phenylpropionic acid-   (S) 2-(4′-trifluoromethanesulfonylamino)phenylpropionic acid-   (R) 2-(4′-methanesulfonylamino)phenylpropionic acid-   (S) 2-(4′-methanesulfonylamino)phenylpropionic acid-   (R) 2-[4′-(2″-propane)sulfonylamino]phenylpropionic acid-   (S) 2-[4′-(2″-propane)sulfonylamino]phenylpropionic acid-   (R) 2-(4′-benzenesulfonylamino)phenylpropionic acid-   (S) 2-(4′-benzenesulfonylamino)phenylpropionic acid-   (R) 2-[4′-(2″-ethyl)benzenesulfonylamino]phenylpropionic acid-   (S) 2-[4′-(2″-ethyl)benzenesulfonylamino]phenylpropionic acid-   (R) 2-[4′-(2″-chloro)benzenesulfonylamino]phenylpropionic acid-   (S) 2-[4′-(2″-chloro)benzenesulfonylamino]phenylpropionic acid-   (R) 2-(4′-benzylsulfonylamino)phenylpropionic acid-   (S) 2-(4′-benzylsulfonylamino)phenylpropionic acid-   (R) 2-(4′-aminosulfonylamino)phenylpropionic acid-   (S) 2-(4′-aminosulfonylamino)phenylpropionic acid-   (R) 2-(4′-trifluoromethanesulfonylmethyl)phenylpropionic acid-   (S) 2-(4′-trifluoromethanesulfonylmethyl)phenylpropionic acid-   (R) 2-(4′-benzenesulfonylmethyl)phenylpropionic acid-   (S) 2-(4′-benzenesulfonylmethyl)phenylpropionic acid.

The compounds of the invention do not interfere with the production ofPGE₂ in murine macrophages stimulated with lipopolysaccharides (LPS, 1μg/ml) over concentration range: 10⁻⁵ to 10⁻⁶ M and are thus devoid ofany inhibitory activity on cyclooxygenases (COX). Due to the absence ofCOX inhibitory activity in both the R and S enantiomers of the described2-phenylpropionic acids, the compounds of the invention represent thefirst example of 2-phenylpropionic acids with the necessary features fora therapeutical use in pathologies related to the exacerbated neutrophilchemotaxis and activation induced by IL-8. The expected metabolic chiralinversion of the R-enantiomers of the present invention yields thecorresponding S-enantiomers that share with the R enantiomers comparablecharacteristics in terms of IL-8 potency and COX selectivity.

The compounds of the invention of formula (I) are generally isolated inthe form of their addition salts with both organic and inorganicpharmaceutically acceptable bases. Examples of such bases are: sodiumhydroxide, potassium hydroxide, calcium hydroxide, (D,L)-Lysine,L-Lysine, tromethamine.

The 3 (meta) and 2 (ortho) substituted 2-arylpropionic acids of formula(I) and their enantiomers are described in WO 01/58852 and in WO00/24710

Acids of formula I as defined above, are obtained by alkylation withstannanes of a polysubstituted 2-phenyl-propionic acid bearing aperfluorobutanesolfonate group in the ortho- or meta- or para-position,as described herein below.

The single enantiomers of 2-arylpropionic acids of formula (I) can beprepared by a total and stereospecific synthesis: the transformation isalso known of racemates into one of the single enantiomers aftertransformation into 2-aryl-2-propyl-ketenes as described by Larse R D etal., J. Am. Chem. Soc., 111, 7650, 1989 and Myers A G, ibidem, 119,6496, 1997. The stereoselective syntheses of 2-arylpropionic acidsmainly relates to the S enantiomers, but they can be modified in orderto obtain the R enantiomers through a convenient selection of the chiralauxiliary agent. For the use of arylalkylketones as substrates for thesynthesis of α-arylalkanoic acids see e.g. B M Trost and J H Rigby, J.Org. Chem., 14, 2926, 1978; for arylation of Meldrum acids see J T Pineyand R A Rowe, Tet. Lett., 21, 965, 1980; the use of tartaric acid aschiral auxiliary agent see Castaldi et al., J. Org. Chem., 52, 3019,1987; for the use of a-hydroxy-esters as chiral reactants, see R DLarsen et al., J. Am. Chem. Soc., 111, 7650, 1989 and U.S. Pat. No.4,940,813 cited here.

A process for the preparation 2-(2-OH-phenyl)-propionic acids and theiresters is described in Italian Patent 1,283,649. An established andefficient method for the preparation of the R enantiomer of(R,S)-2-(5-benzoyl-2-acetoxy)-propionic acid and of the acids of formula(Ia) is the conversion of chlorides of said carboxylic acids into thecorresponding prop-1-ketenes by reaction with a tertiary amine e.g.dimethyl-ethyl-amine, followed by the reaction of the ketene withR(−)pantolactone to yield the esters of R-enantiomers of said acids withR-dihydro-3-hydroxy-4,4-dimethyl-2(3H)furan-2-one. The subsequentsaponification of the ester with LiOH provides the corresponding freeacids.

A general process for the preparation of R-2-arylpropionic acids offormula (Ia) involves, for example, reaction of4-hydroxy-phenylpropionic acids esters or 4-aminophenylpropionic acidsesters with corresponding C₁-C₅-sulphonylchlorides orbenzenesulphonylchlorides in presence of a suitable organic or inorganicbase; or reaction of 4-chloromethylphenylpropionic acids esters withcorresponding C₁-C₅-thiolates or benzenethiolates in presence of asuitable organic or inorganic base as described in detail in the section“General procedure for the synthesis of (S) and(R)-2-[(4′-aryl/alkylsulfonylamino)phenyl]propionic acids of formula Ia”and following sections. A typical preparation of compounds of formula(Ia) involves the reaction of hydroxyarylketones of formula (IIa) monoor polysubstituted by perfluorobutanesulfonylfluoride to yieldperfluorobutanesulfonic esters of formula (IIb) where n is an integerfrom 1 to 9:

The compounds of formula (IIb) are subjected to Willgerodt rearrangementin order to obtain, after esterification and methylation on the alphacarbon, arylpropionic derivatives of formula (IIc) wherein n is aninteger from 1 to 9 and R₃ represents a C₁-C₄ alkyl or C₂-C₄-alkenyl.

The compounds of formula (IIc) are reacted with the appropriatetributylstannane of formula Bu₃SnR₄ where R4 is a linear or branchedC₂-C₆ alkyl; linear or branched C₂-C₆ alkenyl or linear or branchedC₂-C₆ alkynyl, non-substituted or substituted with an aryl group, toobtain corresponding (R,S)-2-arylpropionates of formula (IId).

The alkenyl or alkynyl groups can be hydrogenated in conditions ofcatalytic hydrogenation in order to obtain the correspondents saturatedalkyl groups. The compounds of formula (IId) are subjected to theprocess of de-racemization as described above for conversion of thecorresponding acid chlorides into ketenes that, by reaction withR(−)pantonolactone and subsequent hydrolysis, are converted into thepure R enantiomers; the reaction of the ketene intermediate with thechiral auxiliary S(+)-pantonolactone yields the corresponding pure Senantiomer.

The compounds of the invention of formula (I) were evaluated in vitrofor their ability to inhibit chemotaxis of polymorphonucleate leukocytes(hereinafter referred to as PMNs) and monocytes induced by the fractionsof IL-8 and GRO-α. For this purpose, in order to isolate the PMNs fromheparinized human blood, taken from healthy adult volunteers,mononucleates were removed by means of sedimentation on dextran(according to the procedure disclosed by W. J. Ming et al., J. Immunol.,138, 1469, 1987) and red blood cells by a hypotonic solution. The cellvitality was calculated by exclusion with Trypan blue, whilst the ratioof the circulating polymorphonucleates was estimated on thecytocentrifugate after staining with Diff Quick.

Human recombinant IL-8 (Pepro Tech) was used as stimulating agents inthe chemotaxis experiments, giving practically identical results: thelyophilized protein was dissolved in a volume of HBSS containing 0.2%bovin serum albumin (BSA) so thus to obtain a stock solution having aconcentration of 10⁻⁵ M to be diluted in HBSS to a concentration of 10⁻⁹M, for the chemotaxis assays.

During the chemotaxis assay (according to W. Falket et al., J. Immunol.Methods, 33, 239, 1980) PVP-free filters with a porosity of 5 μm andmicrochambers suitable for replication were used.

The compounds of the invention in formula (I) were evaluated at aconcentration ranging between 10⁻⁶ and 10⁻¹⁰ M; for this purpose theywere added, at the same concentration, both to the lower pores and theupper pores of the microchamber. Evaluation of the ability of thecompounds of the invention of formula (I) to inhibit IL-8-inducedchemotaxis of human monocytes was carried out according to the methoddisclosed by Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989).

By way of example, inhibition data (C=10⁻⁶ M) of some representativecompounds in the IL-8 induced PMN chemotaxis test are reported in thefollowing table:

% inhibition Example Name (C = 10⁻⁶ M) 5 (R,S)2-[3′-isopropylphenyl]propionic acid 51 ± 12 10 (R)2-[3′-isopropylphenyl]propionic acid 43 ± 18 14 (S)2-[3′-isopropylphenyl]propionic acid 50 ± 9  7 (R,S), (R,S)2-[3′-(alpha-methyl-benzyl)- 54 ± 4  phenyl]propionic acid 16 (R,S),(R,S) 2-[3′-(alpha-hydroxy-ethyl)- 57 ± 6  phenyl]propionc acid 18 (R,S)2-[(2′-(2″,6″-dichlorophenyl)- 52 ± 3  amino]phenyl propionic acid 19(R) 2-[(2′-(2″,6″-dichlorophenyl)- 46 ± 14 amino]phenyl propionic acid20 (S) 2-[(2′-(2″,6″-dichlorophenyl)- 50 ± 7  amino]phenyl propionicacid 6 (R,S) 2-[3′-(alpha-ethyl-propyl)phenyl]- 58 ± 2  propionic acid25 (R,S) 2-[(2′-(2″,6″-dichloro)phen- 41 ± 9  oxy)phenyl]propionic acid

The above listed compounds have shown a moderate potency in the GRO-αinduced PMNs chemotaxis test suggesting a selective effect on the CXCR1mediated pathway.

Particularly preferred compounds of the invention are compounds ofFormula Ia, which show the additional property to effectively inhibitthe GROA induced PMN chemotaxis; this activity allows the therapeuticaluse of these compounds in IL-8 related pathologies where the CXCR2pathway is involved specifically or in conjunction with the CXCR1signalling.

In the table below, biological activities of compounds showing highpotency in the inhibition of PMN chemotaxis induced as by IL-8 as by theselective CXCR2 agonist GRO-α are reported.

Some examples of selective GRO-α potent inhibitors are included.

The dual inhibitors of the IL-8 and GRO-α induced biological activitiesare strongly preferred in view of the therapeutical applications ofinterest, but the described compounds selectively acting on CXCR1 IL-8receptor or CXCR2 GRO-α/IL-8 receptor can find useful therapeuticalapplications in the management of specific pathologies as belowdescribed.

Biological activity data on CXCR1 and CXCR2 receptors (% of inhibition)IL-8 GRO-α Example Name (c = 10⁻⁸ M) (c = 10⁻⁸ M) 27 (R)2-(4′-benzenesulfonyl- 49 ± 11 33 ± 11+ amino)phenylpropionic acid 28(R) 2-(4′-methanesulfonyl- 25 ± 7  32 ± 5  amino)phenylpropionic acid 29(R) 2-[4′-(2″-propane)sulfonyl- 54 ± 14 44 ± 12  amino]phenylpropionicacid 30 (R) 2-(4′-trifluoromethanesul-  8 ± 10 40 ± 14 fonylamino)phenylpropionic acid 31 (R) 2-(4′-benzylsulfonyl- 60 ± 10 24± 8  amino)phenylpropionic acid 32 (R) 2-[4′-(2″-chloro)benzenesul- −2 ±10 66 ± 10  fonylamino]phenylpropionic acid 33 (R)2-[4′-(2″-ethyl)benzenesul- 44 ± 14 80 ± 10  fonylamino]phenylpropionicacid 34 (R) 2-(4′-aminosulfonyl- 55 ± 10 2 ± 5  amino)phenylpropionicacid 35 (R) 2-(4′-benzenesulfonyl- 28 ± 11 25 ± 10  oxy)phenylpropionicacid 38 (R) 2-[4′-(2″-propane)sulfonyl- 49 ± 8  46 ± 6 oxy]phenylpropionic acid 37 (R) 2-(4′-trifluoromethane- 62 ± 7  59 ± 10 sulfonyloxy)phenylpropionic acid 36 (R) 2-(4′-benzylsulfonyl- 59 ± 11 25± 11  oxy)phenylpropionic acid 39 (R) 2-[4′-(2″-chloro)benzenesul- 25 ±7  65 ± 10  fonyloxy]phenylpropionic acid 40 (R)2-[4′-(2″-ethyl)benzenesul- 45 ± 13 70 ± 10  fonyloxy]phenylpropionicacid 41 (R) 2-(4′-aminosulfonyloxy)- 65 ± 10 5 ± 7  phenylpropionic acid43 (R) 2-(4′-trifluoromethanesul- 48 ± 7  45 ± 7 fonylmethyl)phenylpropionic acid 42 (R) 2-(4′-benzenesulfonyl- 60 ± 7 52 ± 5  methyl)phenylpropionic acid

All the compounds of the invention demonstrated a high degree ofselectivity towards the inhibition of the IL-8 induced chemotaxiscompared to the chemotaxis induced by C5a (10⁻⁹ M) or f-MLP (10⁻⁸ M).

The compounds of formula (I), evaluated ex vivo in the blood in totoaccording to the procedure disclosed by Patrignani et al., in J.Pharmacol. Exper. Ther., 271, 1705, 1994, were found to be totallyineffective as inhibitors of cyclooxygenase (COX) enzymes.

In almost all cases, the compounds of formula (I) do not interfere withthe production of PGE₂ induced in murine macrophages bylipopolysaccharides stimulation (LPS, 1 μg/mL) at a concentrationranging between 10⁻⁵ and 10⁻⁷ M. Inhibition of the production of PGE₂which may be recorded, is mostly at the limit of statisticalsignificance, and more often is below 15-20% of the basal value. Thereduced effectiveness in the inhibition of the CO constitutes anadvantage for the therapeutical application of compounds of theinvention in as much as the inhibition of prostaglandin synthesisconstitutes a stimulus for the macrophage cells to amplify synthesis ofTNF-α (induced by LPS or hydrogen peroxide) that is an importantmediator of the neutrophilic activation and stimulus for the productionof the cytokine Interleukin-8.

In view of the experimental evidence discussed above and of the roleperformed by Interleukin-8 (IL-8) and congenetics thereof in theprocesses that involve the activation and the infiltration ofneutrophils, the compounds of the invention are particularly useful inthe treatment of a disease such as psoriasis (R. J. Nicholoff et al.,Am. J. Pathol., 138, 129, 1991). Further diseases which can be treatedwith the compounds of the present invention are intestinal chronicinflammatory pathologies such as ulcerative colitis (Y. R. Mahida etal., Clin. Sci., 82, 273, 1992) and melanoma, chronic obstructivepulmonary disease (COPD), bollous pemphigo, rheumatoid arthritis (M.Selz et al., J. Clin. Invest., 87, 463, 1981), idiopathic fibrosis (E.J. Miller, previously cited, and P. C. Carré et al., J. Clin. Invest.,88, 1882, 991), glomerulonephritis (T. Wada et al., J. Exp. Med., 180,1135, 1994) and in the prevention and treatment of damages caused byischemia and reperfusion.

Inhibitors of CXCR1 and CXCR2 activation find useful applications, asabove detailed, particularly in treatment of chronic inflammatorypathologies (e.g. psoriasis) in which the activation of both IL-8receptors is supposed to play a crucial pathophysiological role in thedevelopment of the disease.

In fact, activation of CXCR1 is known to be essential in IL-8-mediatedPMN chemotaxis (Hammond M et al, J Immunol, 155, 1428, 1995). On theother hand, activation of CXCR2 activation is supposed to be essentialin IL-8-mediated epidermal cell proliferation and angiogenesis ofpsoriatic patients (Kulke R et al., J Invest Dermatol, 110, 90, 1998).

In addition, CXCR2 selective antagonists find particularly usefultherapeutic applications in the management of important pulmonarydiseases like chronic obstructive pulmonary disease COPD (D. W P Hay andH. M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247).

It is therefore a further object of the present invention to providecompounds for use in the treatment of psoriasis, ulcerative colitis,melanoma, chronic obstructive pulmonary disease (COPD), bollouspemphigo, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritisand in the prevention and treatment of damages caused by ischemia andreperfusion, as well as the use of such compounds in the preparation ofa medicament for the treatment of diseases as described above.Pharmaceutical compositions comprising a compound of the invention and asuitable carrier thereof, are also within the scope of the presentinvention. The compounds of the invention, together with aconventionally employed adjuvant, carrier, diluent or excipient may, infact, be placed into the form of pharmaceutical compositions and unitdosages thereof, and in such form may be employed as solids, such astablets or filled capsules, or liquids such as solutions, suspensions,emulsions, elixirs, or capsules filled with the same, all for oral use,or in the form of sterile injectable solutions for parenteral (includingsubcutaneous) use. Such pharmaceutical compositions and unit dosageforms thereof may comprise ingredients in conventional proportions, withor without additional active compounds or principles, and such unitdosage forms may contain any suitable effective amount of the activeingredient commensurate with the intended daily dosage range to beemployed.

When employed as pharmaceuticals, the acids of this invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound. Generally,the compounds of this invention are administered in a pharmaceuticallyeffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

The pharmaceutical compositions of the invention can be administered bya variety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Depending on the intendedroute of delivery, the compounds are preferably formulated as eitherinjectable or oral compositions. The compositions for oraladministration can take the form of bulk liquid solutions orsuspensions, or bulk powders. More commonly, however, the compositionsare presented in unit dosage forms to facilitate accurate dosing. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient. Typical unit dosage forms include prefilled,premeasured ampoules or syringes of the liquid compositions or pills,tablets, capsules or the like in the case of solid compositions. In suchcompositions, the acid compound is usually a minor component (from about0.1 to about 50% by weight or preferably from about 1 to about 40% byweight) with the remainder being various vehicles or carriers andprocessing aids helpful for forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Liquid forms, including theinjectable compositions described herebelow, are always stored in theabsence of light, so as to avoid any catalytic effect of light, such ashydroperoxide or peroxide formation. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the acid derivative of formula I in suchcompositions is typically a minor component, frequently ranging between0.05 to 10% by weight with the remainder being the injectable carrierand the like. The mean daily dosage will depend upon various factors,such as the seriousness of the disease and the conditions of the patient(age, sex and weight). The dose will generally vary from 1 mg or a fewmg up to 1500 mg of the compounds of formula (I) per day, optionallydivided into multiple administrations. Higher dosages may beadministered also thanks to the low toxicity of the compounds of theinvention over long periods of time. The above described components fororally administered or injectable compositions are merelyrepresentative. Further materials as well as processing techniques andthe like are set out in Part 8 of “Remington's Pharmaceutical SciencesHandbook”, 18^(th) Edition, 1990, Mack Publishing Company, Easton, Pa.,which is incorporated herein by reference.

The compounds of the invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in the Remington's Handbook asabove.

The present invention shall be illustrated by means of the followingexamples which are not construed to be viewed as limiting the scope ofthe invention.

In the description of the compounds of the invention of formula (I), theconvention has been adopted of indicating the absolute configurations ofany chiral substituents that may be present in the substituent R′ ofsaid compounds with prime signs (e.g., R′, S′, S″ etc.).

Abbreviations: THF: tetrahydrofuran; DMF: dimethylformamide; AcOEt:ethyl acetate, HOBZ: 1-hydroxybenzotriazol, DCC:dicyclohexylcarbodiimide.

Materials and Methods

General Method of Synthesis for 2-aryl-propionic acids of Formula I andR-enantiomers Thereof.

Under stirring, at r.t. and excluding humidity, 12.0 g of anhydrousK₂CO₃ (86.2 mmol) are added to a 80.0 mmol solution of(o,m,p)-hydroxyacetophenone (mono or polysubstituted on the phenyl) inacetone (80 ml). The mixture is stirred for 30′ at r.t. Then a solutionof perfluorobutansulfonylfluoride (15.5 ml 86.1 mmol) in acetone (30 ml)is drip-added and the mixture refluxed for 2 hours. After cooling atr.t. the solid is filtered and the filtrate evaporated to dryness. Theresidue is taken up in EtOAc (100 ml). The organic solution is washedwith a saturated solution of KHCO₃ (20 ml) and then with a saturatedsolution of NaCl (20 ml). After drying on Na₂SO₄ and evaporation of thesolvent the corresponding perflurobutansulfonylester is obtained underthe form of an oil, sufficiently pure to be used in the followingreaction and with practically quantitative yield.

A mixture of the acetophenone perflurobutansulfonyl ester so obtained(80.0 mmol), sulfur (2.95 g, 92.0 mmol) and morpholine (8.0 ml; 92.0mmol) is refluxed for 6 hours. After cooling at r.t. the solution ispoured onto a mixture of ice and 6N HCl (40 ml). It is extracted withCH₂Cl₂ (2×50 ml); the organic extracts are dried over Na₂SO4 and thesolvent is evaporated to give a crude yellow oil that, afterpurification by means of chromatography on silica gel (eluent:n-hexane/EtOAc 9:1) gives the corresponding morpholinamide as atransparent oil (yield 73%).

A solution of morpholinamide (58.0 mmol) in glacial acetic acid (25.0ml) is added to 37% HCl (40 ml) and then it is refluxed for 16 hoursunder stirring. After cooling at r.t., the mixture is filtered from theprecipitate that separated out. After evaporation of the filtrate, theresidue is diluted with H₂O (50 ml) and extracted with EtOAc (2×50 ml).The combined organic extracts are washed with a saturated solution ofNaCl (20 ml), dried over Na₂SO₄ and evaporated at reduced pressure togive an oil from which, by crystallization from n-hexane, provides an(o,m,p)perfluorbutanesulfonate of 2-phenyl-acetic acid in solidcrystalline form (yield 90-93%/o). The subsequent esterification withconcentrated H₂SO₄ in hot absolute ethanol supplies the correspondingethyl ester in practically quantitative yield. In small successiveportions, a 60% suspension of sodium hydride in mineral oil (for a totalof 1.6 g; 66.7 mmol) is added to a solution ofethyl(o,m,p)-perfluorobutansulfonyloxy-2-phenyl-acetate (e.g. 25 mmol)in THF (50 ml) cooled to T=0.5° C. is added gradually. After 15′ methyliodide (1.88 ml; 30.2 mmol) is dripped in and left to react at r.t. for3.5 h. The reaction is stopped by adding a saturated solution to ofNH₄Cl (45 ml); the solvent is evaporated at reduced pressure and theaqueous phase is extracted with CH₂Cl₂ (3×50 ml); the combined organicextracts are washed with a saturated solution of NaCl (200 ml), driedover Na₂SO₄ and evaporated at reduced pressure to give a residue that,after chromatographic purification, provides the ethyl ester of thecorresponding (o,m,p) perfluorobutansulfonyloxy-2-phenyl-propionic acidas a solid (yield 70%).

Starting from the ethyl ester ofethyl(o,m,p)-(nonafluorobutansulfonyloxy)-2-phenylpropionate racematesare prepared of the 2-aryl-propionic acids of formula I by means ofreacting said sulfonates with organostannanes following the methodsdescribed by Mitchell T. N., Synthesis, 803, 1992 and Ritter K.,Synthesis, 735, 1993.

According to the method illustrated above the following compounds wereprepared:

Example 1

2-[3′-(isopropenyl)phenyl]propionic acid

The acid was synthesized starting from ethyl3′-perfluorobutansulfonyloxy-2-phenylpropionate (7.63 mmol) that wasdissolved in N-ethylpirrolidone (30 ml); to the mixture is addedanhydrous LiCl (0.94 g, 22.9 mmol), triphenylarsine (90 mg; 0.3 mmol)and dipalladiumtribenzylidenacetone (0.173 g; 0.15 mmol Pd). After 5′ atr.t. tributylisopropenyltin (2.83 g; 8.55 mmol) is added and thesolution is stirred for 5 h at T=90° C. After cooling the solution tor.t., the mixture is diluted with hexane and a saturated solution of KFis added; after filtration and separation of the phases the organicphase is dried over Na₂SO₄ and evaporated under vacuum. The purificationof the residue by means of flash chromatography gives2-[3′-isopropenylphenyl]ethyl propionate. (Ritter K., Synthesis, 735,1993 and Mitchell T. N., Synthesis, 803, 1992).

1N NaOH (5 ml) was added to a solution of the ester in dioxan (5 ml) andthe solution is stirred at r.t. overnight. After evaporation of theorganic solvent, the mixture is acidified to pH=2 with 2N HCl untilcomplete precipitation of the product, which is isolated, as a whitesolid by filtration.

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.28 (m, 1H); 7.15 (m, 1H); 7.05(m, 2H); 5.02 (s, 2H); 3.75 (m, 1H); 2.34 (m, 1H); 1.8-1.6 (m, 4H); 1.45(d, 3H, 1=7 Hz); 0.78 (s, 3H).

Example 2

2-[3′-(alpha-ethyl-propenyl)phenyl]propionic acid

According to the method reported above, the acid was synthesized byusing as starting reagent tributyl-(α-ethyl)propenyl tin synthesizedaccording to known methods (Ritter K., Synthesis, 735, 1993 and MitchellT. N., Synthesis, 803, 1992).

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.28 (m, 1H); 7.15 (m, 1H); 7.05(m, 2H); 5.5 (m, 1H); 3.75 (m, 1H); 1.8-1.6 (q, 2H); 1.45 (d, 3H, J=7Hz); 0.85 (d, 3H, J=7 Hz); 0.78 (t, 3H, J=7 Hz)

Example 3

3-[3′-(1″-styrenyl)phenyl]propionic acid

According to the method reported above, the acid was synthesized byusing as starting reagent tributyl-α-styrenyl tin synthesized accordingto known methods (Ritter K., Synthesis, 735, 1993 and Mitchell T. N.,Synthesis, 803, 1992).

¹H-NMR (CDCl₃): δ 11.0 (bs, 1H, COOH); 7.38-7.13 (m, 9H); 3.95 (m, 2H);3.81 (m, 1H); 1.72 (d, 3H, J=7 Hz).

Example 4

2-[3′-isobutenyl-phenyl]propionic acid

According to the method reported above the acid was synthesized by usingas starting reagent tributyl isobutenyl-tin synthesized according tomethods (Ritter K., Synthesis, 735, 1993 and Mitchell T. N., Synthesis,803, 1992).

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.28 (m, 1H); 7.15 (m, 1H); 7.05(m, 2H); 5.5 (m, 1H); 3.75 (m, 1H); 1.45 (d, 3H, J=7 Hz); 1.45 (s, 3H);1.35 (s, 3H).

By way of example the preparation of 2-[(3′-isopropyl)phenyl]propionicacid is disclosed

Example 5

A mixture of 2-[3′-(isopropenyl)phenyl]ethyl propionate, obtained by themethod reported above (1 g; 4.6 mmol), 95% ethyl alcohol (10 ml) andPd/C 10% (100 mg) are subjected to catalytic hydrogenation at r.t. andatmospheric pressure until the initial reagent disappears (2 h). Thecatalyst is filtered off on Celite and, after evaporation of thefiltrate, a transparent oil is obtained (0.99 g; 4.5 mmol) that ishydrolysed in a 1N solution of KOH in ethyl alcohol (10 ml) at T=80° C.for 2 h. After cooling at r.t. the solvents are evaporates at reducedpressure; the residue is taken up with EtOAc (20 ml) and it is extractedwith H₂O (3×10 ml); the aqueous phase is acidified to pH=2 with 2N HCland counter-extracted with EtOAc (2×10 ml); the organic extracts arecombined and washed with a saturated solution of NaCl, are dried overNa2SO4 and evaporated at reduced pressure to give2-[(3′-isopropyl)phenyl]propionic acid (0.75 g; 3.6 mmol)

¹H-NMR (CDCl₃): δ 10.5 (bs, 1H, COOH); 7.15-7.08 (m, 4H); 3.55 (m, 1H);2.91 (m, 1H); 1.45 (d, 3H, J=7 Hz); 1.26 (d, 3H, J=7 Hz).

According to the same method the following compounds were prepared:

Example 6

(R,S) 2-[3′-(alpha-ethyl-propyl)phenyl]propionic acid

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.28 (m, 1H); 7.15 (m, 1H); 7.05(m, 2H); 3.75 (m, 1H); 2.34 (m, 1H); 1.8-1.6 (m, 4H); 1.45 (d, 3H, J=7Hz); 0.78 (t, 6H, J=7 Hz).

Example 7

(R,S) 3-[3′-(alpha-methyl)benzyl-phenyl]propionic acid

¹H-NMR (CDCl₃): δ 11.0 (bs, 1H, COOH); 7.38-7.13 (m, 9H); 4.20 (m, 1H);3.78 (m, 1H); 1.72 (d, 3H, J=7 Hz); 1.55 (d, 3H, J=7 Hz).

Example 8

(R,S) 2-[3′-isobutylphenyl]propionic acid

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.28 (m, 1H); 7.15 (m, 1H); 7.05(m, 2H); 3.78 (m, 1H); 2.50 (d, 2H, J=7 Hz); 1.9 (m, 1H); 1.45 (d, 3H,J=7 Hz); 0.98 (d, 6H, J=7 Hz).

Example 9

(R,S) 2-[(3′-cyclohexylmethyl)phenyl]propionic acid

The acid was synthesized according to the procedure reported above, byusing as starting reagents cyclohexylmethyl zinc bromide, commercialreactant and ethyl-3-perfluorobutansulfonyloxy-2-phenylpropionate.

¹H-NMR (CDCl₃): δ 10.15 (bs, 1H, COOH); 7.1 (s, 1H); 7.25-7.35 (m, 3H,);3.75 (q, 1H, J₁=15 Hz, J₂=7 Hz); 2.48 (d, 2H, J=7 Hz); 1.77-1.70 (m,4H); 1.60-1.45 (d, 3H, J=7 Hz+m, 1H); 1.30-1.10 (m, 4H); 1.08-0.90 (m,2H).

Each of the racemates of the acids of formula φ-Ar_(b)—C(CH₃)H—CO₂H isthen transformed into the R enantiomer through the stereospecificpreparation of the corresponding ester with R-pantolactone (via keteneintermediate) operating according to the methods described by Myers A.G. et al., J. Am. Chem. Associates, 119, 6496, 1997 and by Larsen R. D.et al., J. Am. Chem. Associates, 111, 7650 1989.

In this way the following compounds were prepared

Example 10

(R)-2-[(3′-isopropyl)phenyl]-propionic acid

[α]_(D)=−23 (c=0.5; CH₂Cl₂)

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.15-7.10 (m, 4H); 3.65 (m, 1H);2.90 (m, 1H); 1.45 (d, 3H, J=7 Hz); 1.32 (d, 3H, J=7 Hz).

Example 11

(R)-2-[3′-(1″-ethyl-propyl)phenyl]propionic acid

[α]_(D)=−29 (c=0.5; CH₂Cl₂)

¹H-NMR (CDCl₃): δ 10.25 (bs, 1H, COOH); 7.28 (m, 1H); 7.15 (m, 1H); 7.05(m, 2H); 3.75 (m, 1H); 2.34 (m, 1H); 1.8-1.6 (m, 4H); 1.45 (d, 3H, J=7Hz); 0.78 (t, 6H, J=7 Hz).

Example 12

(R) 2-[3′-isobutylphenyl]propionic acid

[α]_(D)=−35 (c=0.5; CH₂Cl₂)

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.28 (m, 1H); 7.15 (m, 1H); 7.05(m, 2H); 3.78 (m, 1H); 2.50 (d, 2H, J=7 Hz); 1.9 (m, 1H); 1.45 (d, 3H,J=7 Hz); 0.98 (d, 6H, J=7 Hz)

Example 13

(R),(R′S′)-3-[(3′-α-methyl)benzylphenyl]propionic acid

[α]_(D)=−49 (c=0.5; CH₂Cl₂)

¹H-NMR (CDCl₃): δ 11.0 (bs, 1H, COOH); 7.38-7.13 (m, 9H); 4.20 (m, 1H);3.78 (m, 1H); 1.72 (d, 3H, J=7 Hz); 1.55 (d, 3H, J=7 Hz).

Following the same procedure above described but using S-pantolactone,the stereospecific preparation of the S enantiomers was achieved:

Example 14

(S)-2-[(3′-isopropyl)phenyl]-propionic acid

[α]_(D)=+24.2 (c=0.5; CH₂Cl₂)

¹H-NMR (CDCl₃): δ 10.1 (bs, 1H, COOH); 7.12-7.07 (m, 4H); 3.64 (m, 1H);2.91 (m, 1H); 1.45 (d, 3H, J=7 Hz); 1.30 (d, 3H, J=7 Hz).

Example 15

(R),(R′,S′))-2-[(3′-α-hydroxybenzyl)phenyl]propionic acid

To a solution of R(−)ketoprofen (0.254 g, 1 mmol) in ethyl alcohol (5ml) triethylamine (0.12 g; 1 mmol) and a catalyst (d/C 5% 0.025 g) areadded; the mixture is hydrogenated at r.t. and atmospheric pressure for3 hours. After removal of the catalyst by filtration on a Celite cake,the filtrate is evaporated and the residue purified on a chromatographiccolumn. The product is obtained as a white solid (yield 85%).

[α]_(D)=−45.7 (c=1; CHCl₃)

¹H-NMR (CDCl₃): δ 7.41-7.3 (m, 3H); 7.31-7.14 (m, 6H); 5.75 (s, 1H);4.02 (bs, 1H, OH); 3.68 (q, 1H, J=7 Hz) 1.4 (d, 3H, J=7 Hz).

Following the same procedure described for the example 15 and startingfrom (R,S)-2-[(3′-acetyl)phenyl]-propionic acid, the following wasobtained:

Example 16

(R,S), (R,S) 2-[3′-(alpha-hydroxy-ethyl)phenyl]propionic acid

¹H-NMR (CDCl₃): δ 7.40-7.15 (m, 4H); 4.90 (q, 1H, J=7 Hz); 3.78 (q, 1H,J=7 Hz); 1.55 (m, 6H).

Example 17

(R),(R′,S′)-2-[3′-α,-hydroxy-α-methyl benzyl)phenyl]propionic acid

To a solution of the methyl ester of R(−)-ketoprofen (0.269, 1 g) inethyl ether (10 ml) a 3.0 M solution of methylmagnesium bromide in ethylether (2 mmol) is added; the resulting solution is refluxed for 2 hours.After cooling of the mixture, the organic phase is washed with a 5%solution of NaH₂PO₄ (2×10 ml), dried over Na₂SO₄ and evaporated undervacuum. The residue obtained is redissolved in a 1:1 mixture of MeOH/1NNaOH (5 ml) and the solution stirred overnight. The organic solvent isremoved under vacuum and the aqueous solution acidified to pH=2; theprecipitate formed is filtered, washed with water. The(R),(R′,S′)-2-[3′-α-hydroxy-α-methylbenzyl)phenyl]propionic acid isobtained as a white powder.

[α]_(D)=−45.3 (c=1; CHCl₃)

¹H-NMR (CDCl₃): δ 7.41-7.3 (m, 3H); 7.31-7.14 (m, 6H); 4.02 (bs, 1H,OH); 3.68 (q, 1H, J=7 Hz); 1.4 (d, 3H, J=7 Hz).

Preparation of (R,S) 2-[2′-(2″,6″-dichlorophenyl)aminophenyl propionicacid (Example 18), (R) 2-[2′-(2′,6″-dichlorophenyl)aminophenyl propionicacid (Example 19) and (S) 2-[2′-(2″,6″-dichlorophenyl)aminophenylpropionic acid (Example 20).

The compound was prepared as a racemic mixture in accordance with themethod reported in Geigy, J R; Gb Patent 1.132.318 (30 Oct. 1968). Theoptical resolution to give examples 19 and 20 was performed by means ofsalification with R(+)-N-methylbenzylamine according to the methoddisclosed in Arzneim. Forsch. 19′ 96, 46:9 891-894 by Akguen et al.

Example 21

Preparation of (R,S)-(2-(3′-benzyl)phenyl propionic acid

1. Methyl 2-bromophenylacetate

To a solution of 2-bromophenyl acetic acid (2 g; 9.30 mmol) in methylalcohol (10 ml) is added a catalytic amount of conc. H₂SO₄, (3 drops);the solvent is stirred at r.t. for 18 h. and is then evaporated. Theresidue oil is taken up with ethyl ether (10 ml); the organic phase isthen washed with —H₂O (3×10 ml), dried over Na₂SO₄ and evaporated togive 2.12 g of methyl ester in the form of a transparent oil.

Yield: quantitative

¹H-NMR (CDCl₃): δ 7.60 (d, 1H, J=7 Hz); 7.28-7.20 (m, 2H); 7.1-7.0 (m,1H); 3.8 (s, 2H); 3.72 (s, 3H).

2. Methyl 2-(2′)bromophenylpropionate

To a solution of diisopropylamine (1.66 ml; 11.8 mmol) in anhydrous THF(30 ml) maintained under stream of Ar and cooled to T=−10° C., is added,by dripping, a solution of n-butyllithium in n-hexane (1.6 M; 7.4 ml;11.8 mmol); the addition is carried out in such way that the temperaturedoes not exceed 0° C. On completion of the addition the mixture isstirred at T=−4° C. for 30 minutes, then methyl 2-bromophenyl acetate(1.9 g; 8.30 mmol) is added in anhydrous THF (8 ml). When the additionis finished, the mixture is stirred at r.t. for 1 h. Then the mixture iscooled again to T=−2° C. and methyl iodide (0.81 ml; 12.75 mmol) isadded. The mixture is stirred at r.t. for 2 h until the starting productdisappears; the ThF is evaporated to dryness, the residue is taken up inCHCl₃ (10 ml) and ml is washed with 1N HCl (3×10) and then with asaturated solution of NaCl (2×10 ml). It is acidified on Na₂SO₄ andevaporated at reduced pressure to give a dark red oily residue (1.95 g;8.02 mmol) of sufficient purity to be used for the following stages.

Yield 96%

¹H-NMR (CDCl₃): δ 7.60 (d, 1H, J=7 Hz); 7.30-7.26 (m, 2H); 7.2-7.15 (m,1H); 4.25 (q, 1H, J=7 Hz); 3.75 (s, 3H); 1.75 (d, 3H, J=7 Hz).

3. Methyl 2-(2′-)benzylphenylpropionate

Zinc powder (2.412 g; 36.9 mmol) is loaded into a flask under Ar. Theflask is cooled off to T=0-4° C. with an ice/water bath and a solutionof benzyl bromide (2.109 g; 12.3 mmol) in anhydrous TBF (10 ml) is addedby means of slow dripping. The mixture is stirred at such temperaturefor 3 h until the starting product disappears. In parallel, in anotherflask under Ar tetrakis(triphenylphosfine)palladium (410 g; 0.35 mmol)and methyl 2-(2′-bromophenyl)propionate (1.9 g; 7.8 mmol) is loaded; thesolution of organotin previously obtained is added and, when thedripping is finished, the solution is raised to reflux temperature for18 h. After cooling at r.t. the mixture is diluted with 0.1N HCl (10 ml)and ethyl ether (15 ml) is added; they are shaken and the two phases areseparated, the aqueous phase is again extracted with ethyl ether (3×15ml); the organic extracts, combined, are washed with a saturatedsolution of NaHCO₃, dried over Na₂SO₄ and evaporated at reduced pressureto give a waxy residue that, after trituration with isopropyl etherovernight and filtration under vacuum, gives methyl2-(2′-benzylphenyl)propionate in the form of a white solid (1.52 g; 6mmol).

Yield 77%

¹H-NMR (CDCl₃): δ 7.50-7.25 (m, 5H); 7.24-7.15 (m, 2H); 7.10-7.05 (m,2H); 4.25 (q, 1H, J=7 Hz); 4.15 (s, 2H); 3.75 (s, 3H); 1.55 (d, 3H, J=7Hz).

4. (R,S) 2-(2′-Benzylphenyl)propionic acid

Methyl 2-(2′-benzylphenyl)propionate (1.5 g; 5.9 mmol) is dissolved inmethyl alcohol (5 ml). 1M NaOH (7.1 ml) is added to the solution and theresulting solution is refluxed for 3 h; then it is stirred at r.t. for18 h. The alcohol is then evaporated at reduced pressure and the residueis taken up with water; the aqueous phase is brought to pH=1 with 1N HCland extracted with ethyl ether (3×5 ml). The combined organic extractsare washed with a saturated solution of NaHCO₃, dried over Na₂SO₄ andevaporated at reduced pressure to give (R,S)2-(2′-benzylphenyl)propionic acid (1.06 g; 4.42 mmol) as a clear yellowoil.

Yield 75%

¹H-NMR (CDCl₃): δ 9.25 (bs, 1H, COOH); 7.55-7.35 (m, 5H); 7.24-7.15 (m,2H); 7.10-7.05 (m, 2H); 4.25 (q, 1H, J=7 Hz); 4.15 (s, 2H); 1.50 (d, 3H,J=7 Hz).

According to the same method the following compounds were prepared

Example 22

(R,S) 2-[2′-[2″-chloro)benzyl]phenyl propionic acid

¹H-NMR (CDCl₃): δ 10.0 (bs, 1H, COOH); 7.40-7.35 (m, 1H); 7.34-7.25 (m,3H); 7.20-7.15 (m, 2H); 7.10-7.00 (m, 1H); 6.95-6.80 (m, 1H); 4.20 (q,1H, J=7 Hz); 4.12 (s, 2H); 1.53 (d, 3H, J=7 Hz)

Example 23

(R,S) 2-[2′-(2″,6″-dichloro)benzyl phenyl propionic acid

¹H-NMR (CDCl₃): δ 9.55 (bs, 1H, COOH); 7.40-7.30 (d, 2H, J=8 Hz);7.27-7.15 (m, 4H); 6.70-6.60 (d, 1H, J=8 Hz); 4.27 (s, 2H); 4.15 (q, 1H,J=7 Hz); 1.55 (d, 3H, J=7 Hz).

Example 24

Preparation of (R,S) 2-(2′-phenoxy)phenyl propionic acid

1. Methyl 2-(2′-hydroxy)phenyl propionate

To a solution of 2-(2′-hydroxy)phenyl propionic acid (2 g; 12 mmol)(prepared according to methods known in the literature) in methylalcohol (10 ml) a catalytic amount of conc. H₂SO₄ (3 drops) is added;the mixture is stirred at r.t. for 18 h. The solvent is then evaporatedand the residual oil is taken up with ethyl ether (10 ml); the organicphase is then washed with H₂O (3×10 ml), dried over Na₂SO₄ andevaporated to give 2.17 g (12 mmol) of methyl ester in the form of atransparent oil.

Quantitative Yield

¹H-NMR (CDCl₃): δ 7.30-7.26 (m, 2H); 7.2-7.15 (m, 1H); 6.75 (d, 1H, J=7Hz); 5.55 (bs, 1H, OH); 4.15 (q, 1H, J=7 Hz); 3.70 (s, 3H); 1.75 (d, 3H,J=7 Hz).

2. Methyl 2-[2′-(2″-chloro)-phenoxy]phenylpropionate

Methyl 2-(2′-hydroxy)phenylpropionate (2 g; 11.1 mmol) is dissolved inCHCl₃ (60 ml); 2-chlorophenyl boronic acid (7.71 g; 49.3 mmol), copperacetate (3.24 g; 17.82 mmol) and triethylamine (7.7 ml; 5.54 mmol) areadded in sequence. The solution thus obtained is refluxed for 24 h,until the starting product disappears. After cooling at r.t. the saltsare filtered off on a Celite cake; the filtrate is washed with 2N HCl(3×50 ml) and with a saturated solution of NaCl (2×35 ml); the organicphase is dried over Na₂SO₄ and is evaporated at reduced pressure to givea dark oily residue that is purified by means of flash-chromatography(eluent CHCl₃CH₃OH 9:1). Methyl 2-[2′(2″-chloro)phenoxy]phenylpropionate(1.38 g; 5 mmol) is recovered in the form of transparent oil.

Yield 45%

¹H-NMR (CDCl₃): δ 7.45-7.22 (m, 4H); 7.15-7.08 (m, 2H); 7.05-6.95 (m,2H); 6.92-6.88 (m, 1H); 4.28 (q, 1H, J=7 Hz); 3.85 (s, 3H); 1.65 (d, 3H,J=7 Hz).

3. (R,S) 2-[2′-(2″-chloro)phenoxy]phenyl propionic acid

Methyl 2-[2′-(2″-chloro)phenoxy]phenylpropionate (1.3 g; 4.7 mmol) isdissolved in dioxan (15 ml). 1M NaOH (4.7 ml) is added to the solutionand the solution is stirred at r.t. for 18 h. The solvent is evaporatedat reduced pressure and the residue is taken up with water; the aqueousphase is taken to pH=1 with conc. H₂SO₄ conc. and extracted with CHCl₃(3×15 ml). The combined organic extracts are washed with a saturatedsolution of NaHCO₃, then with a saturated solution of NaCl, dried overNa₂SO₄ and evaporated at reduced pressure to give (R,S)2-[2′-(2″-chloro)phenoxy]phenyl]propionic acid (1.18 g; 4.5 mmol) as aclear yellow waxy solid.

Yield 96%

¹H-NMR (CDCl₃): δ 7.45-7.22 (m, 4H); 7.15-7.08 (m, 2H); 7.05-6.95 (m,2H); 6.92-6.88 (m, 1H); 3.95 (q, 1H, J=7 Hz); 1.50 (d, 3H, J=7 Hz).

According to the same procedure the following compound was prepared

Example 25

(R,S) 2-[2′-(2″,6″-dichloro)phenoxy]phenylpropionic acid

¹H-NMR (CDCl₃): δ 9.40 (bs, 1H, COOH); 7.40-7.30 (d, 2H, J=8 Hz);7.27-7.15 (m, 4H); 6.70-6.60 (d, 1H, J=8 Hz); 3.90 (q, 1H, J=7 Hz); 1.55(d, 3H, J=7 Hz).

Example 26

Preparation of 2-(3-methylindane-5-yl)propanoic acid

Starting from 6-methoxy-1-indanone (commercial reagent) the requiredacid was synthesized according to methods known in the literature. Inparticular 6-methoxy-1-indanone was subjected to the Wittig reaction(yield 80%) with the ilide of triphenylmethylphosfonium bromide to givethe esomethylene derivative that, by catalytic hydrogenation (H₂/Pd 5%,P atm.; yield 95%) was reduced to methyl indanoyl derivative. Thesubstrate, by treatment with BBr₃, was deprotected on the phenolic group(yield>95%/o); by processing the intermediate withtrifluoromethansulfonic anhydride the corresponding triflate wasobtained (yield 80%) to be subjected to cross-coupling reaction (Stillereaction previously described) with the methyl2-tributylstannylacrylate. The reaction proceeds with good yield (40%)and the 2-methoxycarbonyl isopropen-2-yl intermediate thus obtained,after catalytic hydrogenation for the reduction of the double bond andsaponification in well known conditions with KOH/EtOH, allows to obtain2-(3-methylindane-5-yl)propanoic acid with high yields.

Yield 90%

¹H-NMR (CDCl₃): δ 7.15-7.05 (m, 3H); 3.75 (m, 1H); 3.15 (m, 1H);2.95-2.70 (m, 2H); 2.32 (m, 1H); 1.78-1.58 (m, 1H); 1.50 (d, 3H, J=7Hz); 1.35 (d, 3H, J=7 Hz).

General Procedure for the Synthesis of (S) and(R)-2-[(4′-aryl/alkylsulfonylamino)phenyl]propionic acids of Formula Ia

The separation of the two enantiomers of the commercial reagent2-(4′-nitrophenyl)propionic acid is achieved by crystallisation of thecorresponding S-(−) or R-(+)-α-phenylethylammonium salts in ethanolicsolution as described in Akgun H. et al., Arzneim.-Forsch./Drug Res.,46(II), Nr. 9, 891-894 (1996).

(S)-2-(4′-nitrophenyl)propionic acid

[α]_(D)=+43.9° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 8.15 (d, 2H, J=7 Hz); 7.47 (d, 2H, J=7 Hz); 3.95 (bs,1H, COOH); 3.78 (m, 1H); 1.52 (d, 3H, J=7 Hz).

(R)-2-(4′-nitrophenyl)propionic acid

[α]_(D)=−43.5° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 8.12 (d, 2H, J=7 Hz); 7.49 (d, 2H, J=7 Hz); 3.90 (bs,1H, COOH); 3.81 (m, 1H); 1.50 (d, 3H, J=7 Hz).

4′-nitrophenylpropionic acids methyl esters

(R)-2-(4′-nitrophenyl)propionic acid (4 mmol) is dissolved in methanol(40 mL) and 96% H₂SO₄ is added dropwise (0.5 mL). The resulting solutionis left stirring overnight. After solvents evaporation the oily residueis dissolved in diethyl ether and the organic phase is washed with asat. solution of NaHCO₃ (2×30 mL), dried over Na₂SO₄ and evaporatedunder reduced pressure to give the desired product as pale yellow oil.

(R)-2-(4′-nitrophenyl)propionic acid methyl ester

[α]_(D)=−48.3° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 8.12 (d, 2H, J=7 Hz); 7.49 (d, 2H, J=7 Hz); 3.75 (m,1H); 3.70 (s, 3H); 1.51 (d, 3H, J=7 Hz).

(S)-2-(4′-nitrophenyl)propionic acid methyl ester

[α]_(D)=+49° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 8.11 (d, 2H, J=7 Hz); 7.49 (d, 2H, J=7 Hz); 3.78 (m,1H); 3.68 (s, 3H); 1.51 (d, 3H, J=7 Hz).

(S) and (R)-2-(4′-aminophenyl)propionic acids methyl esters

Both the compounds are prepared by nitro group reduction as described inRam S. et al., Tetrahedron Lett., 25, 3415 (1984) and in Barrett A. G.M. et al., Tetrahedron Lett., 29, 5733 (1988).

(S)-2-(4′-aminophenyl)propionic acid methyl ester

[α]_(D)=+16.5° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.85 (d, 2H, J=7 Hz); 7.45 (d, 2H, J=7 Hz); 3.81 (m,1H); 3.67 (s, 3H); 1.62 (d, 3H, J=7 Hz).

(R)-2-(4′-aminophenyl)propionic acid methyl ester

[α]_(D)=−17.1° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.85 (d, 2H, J=7 Hz); 7.45 (d, 2H, J=7 Hz); 3.81 (m,1H); 3.66 (s, 3H); 1.65 (d, 3H, J=7 Hz).

(R)-2-[(4′-aryl/alkylsulfonylamino)phenyl]propionic acids

To a solution of the above described (R)-2-(4′-aminophenyl)propionicacid methyl ester (10 mmol) in acetone (20 mL), dry pyridine (15 mmol)or equivalent organic/inorganic base and arylsulfonyl (or alkylsulfonyl)chloride (10 mmol) are added and the resulting solution is left stirringovernight. After solvent evaporation the oily residue is dissolved inCHCl₃ (30 mL) and the organic phase is washed with water (3×30 mL),dried over Na₂SO₄ and evaporated to give the desired product pure assolid after treatment at room temperature overnight in isopropyl etherand filtration under vacuum of the precipitate.

To a solution of the methyl ester (6 mmol) in CH₃OH (25 mL), 2N NaOH (12mmol) is added and the resulting mixture is left stirring overnight atroom temperature. CH₃OH is evaporated and the aqueous basic layer isacidified to pH=2 by dropping 12 N HCl; ethyl acetate is added and thetwo phases are separated. The organic extracts are washed back withwater (3×20 mL), dried over Na₂SO₄ and evaporated under reduced pressureto give the product isolated pure as solid after treatment at roomtemperature overnight in n-hexane and filtration under vacuum of theprecipitate (yield 75%-100%).

According the above described procedure the following compounds havebeen synthesised:

Example 27

(R) 2-(4′-(benzenesulfonylamino)phenylpropionic acid

[α]_(D)=−56.5° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 9.40 (bs, 1H, SO₂NH); 7.70 (d, 2H, J=8 Hz); 7.30 (m,3H); 7.05 (d, 2H, J=8 Hz); 6.92 (d, 2H, J=8 Hz); 3.45 (q, 1H, J=7 Hz);1.22 (d, 3H, J=7 Hz).

Example 28

(R) 2-(4′-methanesulfonylamino)phenylpropionic acid

[α]_(D)=−124.3° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.48 (bs, 1H, SO₂NH); 7.35 (d, 2H, J=8 Hz); 7.18 (d,2H, 3=8 Hz); 6.55 (bs, 1H, SO₂NH); 3.80 (q, 1H, J=7 Hz); 3.00 (s, 3H);1.55 (d, 3H, 37 Hz).

Example 29

(R) 2-[4′-(2″-propane)sulfonylamino]phenylpropionic acid

[α]_(D)=−110° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ7.21 (d, 2H, J=8 Hz); 7.05 (d, 2H, J=8 Hz); 6.20 (bs,1H, SO₂NH); 3.65 (q, 1H, J=7 Hz); 3.23 (m, 1H); 1.50 (d, 3H, J=7 Hz);1.30 (d, 6H, J=7 Hz).

Example 30

(R) 2-(4′-trifluoromethanesulfonylamino)phenylpropionic acid

[α]_(D)−−84.5° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.25-7.05 (m, 4H); 7.00 (bs, 1H, SO₂NH); 3.60 (q, 1H,J=7 Hz); 1.41 (d, 3H, J=7 Hz).

Example 31

(R) 2-(4′-benzylsulfonylamino)phenylpropionic acid

[α]_(D)=−47° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.53 (m, 5H); 7.31 (d, 2H, J=7 Hz); 7.15 (bs, 1H,SO₂NH); 7.02 (d, 2H, J=7 Hz); 4.65 (s, 2H); 3.80 (m, 1H); 1.55 (d, 3H,J=7 Hz).

Example 32

(R) 2-[4′-(2″-chloro)benzenesulfonylamino]phenylpropionic acid

[α]_(D)=−81.5° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.95 (d, 1H, J=8 Hz); 7.40 (m, 2H); 7.22 (m, 1H); 7.10(m, 2H); 6.95 (m, 2H+SO₂NH); 3.55 (q, 1H, J=7 Hz); 1.35 (d, 3H, J=7 Hz).

Example 33

(R) 2-[4′-(2″-ethyl)benzenesulfonylamino]phenylpropionic acid

Preparation of 2-ethylbenzenesulfonyl chloride

Starting from commercial 2-ethylbenzenethiol, the related sulfonic acidis prepared as described in Trahanovsky W. S., “Oxidation in OrganicChemistry”, Vol. 5-D, 201-203 Academic Press, Inc, (London), 1982.Treatment of the sulfonic acid with excess thionyl chloride gives the2-ethylbenzenesulfonyl chloride pure to be used in the condensation withR(−)-2-(4′-aminophenyl)propionic acid methyl ester.

[α]_(D)=−95° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 9.30 (bs, 1H, SO₂NH); 7.70 (d, 2H, J=8 Hz); 7.25 (m,4H); 7.08 (d, 2H, J=8 Hz); 3.41 (q, 1H, J=7 Hz); 2.70 (q, 2H, J=8 Hz);1.42 (d, 3H, J=8 Hz); 1.22 (d, 3H, J=7 Hz).

Example 34

(R) 2-(4′-aminosulfonylamino)phenylpropionic acid

[α]_(D)=−110° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.95 (d, 2H, J=8 Hz); 7.54 (bs, 2H, NSO₂NH ₂); 6.98(m, 2H+SO₂NH); 3.57 (q, 1H, J=7 Hz); 1.30 (d, 3H, J=7 Hz).

General Procedure for the Synthesis of (S) and(R)-2-[(4′-aryl/alkylsulfonyloxy)phenyl]propionic Acids of Formula Ia

The separation of the two enantiomers of the commercial reagent2-(4′-hydroxyphenyl)propionic acid is achieved by crystallisation of thecorresponding S(−) or R(+)-α-phenylethylammonium salts in ethanolicsolution as described in Akgun H. et al., Arzneim.-Forsch./Drug Res.,46(II), Nr. 9, 891-894 (1996).

(S)-2-(4′-hydroxyphenyl)propionic acid

[α]_(D)=+12° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.31 (d, 2H, J=7 Hz); 7.05 (d, 2H, J=7 Hz); 6.25 (bs,1H, OH); 3.80 (q, 1H, J=7 Hz); 1.52 (d, 3H, J=7 Hz).

(R)-2-(4′-hydroxyphenyl)propionic acid

[α]_(D)=−12.5° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.30 (d, 2H, J=7 Hz); 7.07 (d, 2H, J=7 Hz); 6.35 (bs,1H, OH); 3.75 (q, 1H, J=7 Hz); 1.50 (d, 3H, J=7 Hz).

(R) and (S)-2-(4′-hydroxyphenyl)propionic acid methyl esters

(2R)-2-(4′-hydroxyphenyl)propionic acid (4 mmol) is dissolved in CH₃OH(40 mL) and conc. H₂SO₄ is added dropwise (0.5 mL). The resultingsolution is left stirring overnight. After solvents evaporation the oilyresidue is dissolved in diethyl ether and the organic phase is washedwith a sat. solution of NaHCO₃ (2×30 mL), dried over Na₂SO₄ andevaporated under reduced pressure to give the desired product as paleyellow oil.

(R) 2-(4′-hydroxyphenyl)propionic acid methyl ester

[α]_(D)=−78° (c=2; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.32 (d, 2H, J=7 Hz); 7.10 (d, 2H, J=7 Hz); 6.40 (bs,1H, OH); 3.70 (m, 4H); 1.53 (d, 3H, J=7 Hz).

(R) 2-[(4′-aryl/alkylsulfonyloxy)phenyl]propionic acids

A mixture of the above described (2R)-2-(4′-hydroxyphenyl)propionic acidmethyl ester (2 mmol) and arylsulfonyl (or alkylsulfonyl) chloride (2mmol) in dry pyridine (1 mL) or in presence of equivalentorganic/inorganic base is warmed at T=60° C. for 24 hours. After coolingat room temperature the reaction mixture is poured into 1 N HCl (5 mL)and the aqueous solution is extracted with CH₂Cl₂ (3×10 mL). Thecollected organic extracts are washed back with 1N NaOH (2×10 mL), driedover Na₂SO₄ and evaporated under reduced pressure to give a cruderesidue pure enough to be used for the following step (yield 80-92%).

A mixture of the crude methyl ester (1.85 mmol), glacial acetic acid(2.5 mL) and 37% HCl (0.5 mL) is refluxed for 18 hours. All the solventsare evaporated off, the oily residue is dissolved in CH₂Cl₂ (5 mL) andthe organic phase is washed with 1N NaOH (2×5 mL) and with water (2×10mL), dried over Na₂SO₄ and evaporated under reduced pressure to givepure (2R) aryl (or alkyl)sulfonyloxyphenyl propionic acids in aquantitative yield

According the above described procedure the following compounds havebeen synthesised:

Example 35

(R) 2-(4′-benzenesulfonyloxy)phenylpropionic acid

[α]_(D)=−66.20 (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.92 (d, 2H, J=7 Hz); 7.70 (t, 1H, J=7 Hz); 7.57 (t,2H, J=7 Hz); 7.25 (d, 2H, J=7 Hz); 6.95 (d, 2H, J=7 Hz); 3.75 (q, 1H,J=7 Hz); 1.50 (d, 3H, J=7 Hz).

Example 36

(R) 2-(4′-benzylsulfonyloxy)phenylpropionic acid

[α]_(D)=−84.6° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.50 (m, 5H); 7.28 (d, 2H, J=7 Hz); 7.05 (d, 2H, J=7Hz); 4.53 (s, 2H); 3.77 (m, 1H); 1.52 (d, 3H, J=7 Hz).

Example 37

(R) 2-(4′-trifluoromethanesulfonyloxy)phenylpropionic acid

[α]_(D)=−28.50 (c=1; CH₃OH);

¹H-NMR (CDCl₃): δ 7.45 (d, 2H, J=7 Hz); 7.22 (d, 2H, J=7 Hz); 3.82 (q,1H, J=7 Hz); 1.51 (d, 3H, J=7 Hz).

Example 38

(R) 2-[4′-(2″-propane)sulfonyloxy]phenylpropionic acid

[α]_(D)=−42.8° (c=1; CH₃OH);

¹H-NMR (CDCl₃): δ 7.41 (d, 2H, J=7 Hz); 7.25 (d, 2H, J=7 Hz); 3.82 (q,1H, J=7 Hz); 3.45 (q, 1H, J=7 Hz); 1.52 (m, 9H).

Example 39

(R) 2-[4′-(2″-chloro)benzenesulfonyloxy]phenylpropionic acid

[α]_(D)=−43° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.90 (d, 1H, J=8 Hz); 7.44 (m, 2H); 7.20 (m, 1H); 7.12(m, 2H); 6.95 (d, 2H, J=8 Hz); 3.52 (q, 1H, J=7 Hz); 1.38 (d, 3H, J=7Hz).

Example 40

(R) 2-[4′-(2″-ethyl)benzenesulfonyloxy]phenylpropionic acid

Preparation of 2-ethylbenzenesulfonyl chloride

Starting from commercial 2-ethylbenzenethiol, the related sulfonic acidis prepared as described in Trahanovsky W. S., “Oxidation in OrganicChemistry”, Vol. 5-D, 201-203 Academic Press, Inc, (London), 1982.Treatment of the sulfonic acid with excess thionyl chloride gives the2-ethylbenzenesulfonyl chloride pure to be used in the condensation with(R)-2-(4′-hydroxyphenyl)propionic acid methyl ester.

[α]_(D)=−1040 (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.71 (d, 2H, J=8 Hz); 7.25 (m, 4H); 7.12 (d, 2H, J=8Hz); 3.44 (q, 1H, J=7 Hz); 2.71 (q, 2H, J=8 Hz); 1.45 (d, 3H, J=8 Hz);1.20 (d, 3H, J=7 Hz).

Example 41

(R) 2-(4′-aminosulfonyloxy)phenylpropionic acid

[α]_(D)=−91.5° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.95 (d, 2H, J=8 Hz); 7.84 (bs, 2H, NSO₂NH ₂); 6.95(d, 2H, J=8 Hz); 3.61 (q, 1H, J=7 Hz); 1.35 (d, 3H, J=7 Hz).

Procedure for the Synthesis of (S) and(R)-2-[(4′-aryl/alkylsulfonylmethyl)phenyl]propionic acids of Formula Ia

Example 42

(R) 2-(4′-benzenesulfonylmethyl)phenylpropionic acid

The title product is prepared by a multi-step synthesis starting fromthe commercial (R)-2-phenylpropionic acid. Following the proceduredescribed in EP 0 889 020 (Ex. 4),(R)-2-[(4′-chloromethyl)phenyl]propionic acid is prepared in good yield.The acid is transformed into the methyl ester by usual procedure and theester is added to a cooled mixture of benzenethiol/potassiumtert-butoxide/18-crown-6 (1:1.1:0.95) and, after overnight reaction andusual work-up (washings with water, drying over Na₂SO₄ and solventevaporation), the pure benzenethiomethyl derivative is isolated and usedin the following oxidative step. The oxidation to the related sulfone by2 equivalents of 3-chloroperoxybenzoic acid and the final treatment withNaOH/dioxane at room temperature allow to isolate the desired product ingood final yield (65% starting from(R)-2-[(4′-chloromethyl)phenyl]propionic acid).

[α]_(D)=−125° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.90 (m, 2H); 7.44-7.20 (m, 3H); 7.12 (d, 2H, J=8 Hz);6.95 (d, 2H, J=8 Hz); 3.72 (s, 2H); 3.55 (q, 1H, J=7 Hz); 1.43 (d, 3H,J=7 Hz).

Example 43

(R) 2-(4′-trifluoromethanesulfonylmethyl)phenylpropionic acid

Following the procedure described in U.S. Pat. No. 5,245,039 (14 Sep.1993) and starting from (R)-2-[(4′-chloromethyl)phenyl]propionic acidmethyl ester, the related (R)-2-[(4′-thiomethyl)phenyl]propionic acid isobtained in high yield (85%). By treatment of the thiolate (“in situ”generated with 1 equivalent of potassium tert-butoxide) with thecommercial trifluoromethyl iodide, the trifluoromethanethiomethylderivative is obtained. The following oxidation to the sulfonederivative (by treatment with 2 equivalents of 3-chloroperoxybenzoicacid) and the final ester hydrolysis by NaOH/dioxane at room temperatureallow to isolate the desired product in quite good final yield (47%starting from (R)-2-[(4′-chloromethyl)phenyl]propionic acid).

[α]_(D)=−86° (c=1; abs. EtOH);

¹H-NMR (CDCl₃): δ 7.14 (d, 2H, J=8 Hz); 7.02 (d, 2H, J=8 Hz); 3.85 (s,2H); 3.51 (q, 1H, J=7 Hz); 1.48 (d, 3H, J=7 Hz).

List of the Examples Structures

Example Structure formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

1. A method for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bollous pemphigo, idiopathic fibrosis, glomerulonephritis and for the treatment of damage caused by ischemia and reperfusion, which comprises: administering to a patient in need thereof an effective amount of a (R,S)-2-aryl-propionic acid compound of formula (I), or the single (R) or (S) enantiomer:

or a pharmaceutically acceptable salt thereof, wherein Ar is a phenyl ring substituted by: a group in the 3 (meta) position selected from a linear or branched C₁-C₅ alkyl, C₂-C₅-alkenyl or C₂-C₅-alkynyl group optionally substituted by C₁-C₅-alkoxycarbonyl, substituted or not-substituted phenyl, linear or branched C₁-C₅ hydroxyalkyl, aryl-hydroxymethyl, or a group in the 3 (meta) position selected from a linear or branched C₁-C₅ alkyl group, optionally substituted by C₁-C₅-alkoxycarbonyl, substituted or not-substituted phenyl, linear or branched C₁-C₅ hydroxyalkyl, aryl-hydroxymethyl, together with a substituent in the ortho or para position that comprises a benzene ring or a saturated or unsaturated, substituted or non-substituted bicycloaryl group; or a group in the 4 (para) position selected from C₁-C₅-acyloxy, substituted or not-substituted benzoyloxy, C₁-C₅-acylamino, substituted or not-substituted benzoylamino, C₁-C₅-sulfonyloxy, substituted or not-substituted benzenesulfonyloxy, C₁-C₅-alkanesulfonylamino, substituted or not-substituted benzenesulfonylamino, C₁-C₅-alkanesulfonylmethyl, substituted or not-substituted benzenesulfonylmethyl, C₃-C₆-cycloalkyl, 2-furyl, 3-tetrahydrofuryl, 2-thiophenyl, 2-tetrahydrothiophenyl, C₁-C₈ (alkanoyl)-C₁-C₅-alkylamino, C₁-C₈ (cycloalkanoyl)-C₁-C₅-alkylamino or C₁-C₈ (arylalkanoyl)-C₁-C₅-alkylamino; or a group in the 2 (ortho) position selected from substituted or not-substituted arylmethyl, substituted or not-substituted aryloxy, or substituted or not-substituted arylamino, wherein the substituents of the aryl group are selected from C₁-C₄ alkyl, C₁-C₄-alkoxy, chlorine, fluorine and/or trifluoromethyl groups, with the exception of (R,S)-2-(2′-benzylphenyl)-propionic acid.
 2. The method of claim 1, wherein Ar is: a phenyl ring 3-substituted by a group selected from: isoprop-1-en-1-yl, ethyl, isopropyl, pent-2-en-3-yl, pent-3-yl, 1-phenyl-ethylen-1-yl, α-methylbenzyl, α-hydroxybenzyl, α-hydroxyethyl, α-hydroxypropyl, or a bicyclic aryl group; or Ar is a phenyl ring 4-substituted by a group selected from: trifluoromethanesulfonyloxy, 2-propanesulfonyloxy, benzylsulfonyloxy, benzenesulfonyloxy, 2′-ethylbenzenesulfonyloxy, 2′-chlorobenzenesulfonyloxy, methanesulfonylamino, trifluoromethanesulfonylamino, 2-propanesulfonylamino, benzylsulfonylamino, benzenesulfonylamino, 2′-ethylbenzenesulfonylamino, aminosulfonylmethyl, 2′-chlorobenzenesulfonylamino, trifluoromethanesulfonylmethyl, benzenesulfonylmethyl, aminosulfonyloxy, or aminosulfonylamino; or Ar is a phenyl ring 2-substituted by a group selected from: 2-(2,6-dichloro-phenylamino)-phenyl, 2-(2,6-dichloro-phenyl-amino)-5-chloro-phenyl, 2-(2,6-dichloro-3-methyl-phenyl-amino)-phenyl, 2-(3-trifluoromethyl-phenyl-amino)-phenyl, 2-(2,6-dichloro-phenoxy)-phenyl, 2-(2-chloro-phenoxy)-phenyl, 2-(2,6-dichloro-benzyl)-phenyl, or 2-(2-chloro-benzyl)-phenyl.
 3. The method of claim 2, wherein said compound is selected from the group consisting of: (R,S) 2-[3′-(alpha-ethyl-propyl)phenyl]propionic acid, (R) 2-[3′-(alpha-ethyl-propyl)phenyl]propionic acid, (S) 2-[3′-(alpha-ethyl-propyl)phenyl]propionic acid, 2-[3′-(alpha-hydroxy-ethyl)phenyl]propionic acid, and the single diastereoisomers thereof, 2-[3′-(alpha-hydroxy-propyl)phenyl]propionic acid and the single diastereoisomers thereof, (R,S) 2-[3′-isopropylphenyl]propionic acid, (R) 2-[3′-isopropylphenyl]propionic acid, (S) 2-[3′-isopropylphenyl]propionic acid, (R) 2-(4′-trifluoromethanesulfonyloxy)phenylpropionic acid, (S) 2-(4′-trifluoromethanesulfonyloxy)phenylpropionic acid, (R) 2-(4′-benzenesulfonyloxy)phenylpropionic acid, (S) 2-(4′-benzenesulfonyloxy)phenylpropionic acid, (R) 2-[4′-(2″-ethyl)benzenesulfonyloxy]phenylpropionic acid, (S) 2-[4′-(2″-ethyl)benzenesulfonyloxy]phenylpropionic acid, (R) 2-[4′-(2″-chloro)phenylsulfonyloxy]phenylpropionic acid, (S) 2-[4′(2″-chloro)phenylsulfonyloxy]phenylpropionic acid, (R) 2-[4′-(2″-propane)sulfonyloxy]phenylpropionic acid, (S) 2-[4′-(2″-propane)sulfonyloxy]phenylpropionic acid, (R) 2-(4′-benzylsulfonyloxy)phenylpropionic acid, (S) 2-(4′-benzylsulfonyloxy)phenylpropionic acid, (R) 2-(4′-aminosulfonyloxy)phenylpropionic acid, (S) 2-(4′-aminosulfonyloxy)phenylpropionic acid, (R) 2-(4′-trifluoromethanesulfonylamino)phenylpropionic acid, (S) 2-(4′-trifluoromethanesulfonylamino)phenylpropionic acid, (R) 2-(4′-methanesulfonylamino)phenylpropionic acid, (S) 2-(4′-methanesulfonylamino)phenylpropionic acid, (R) 2-[4′-(2″-propane)sulfonylamino]phenylpropionic acid, (S) 2-[4′-(2″-propane)sulfonylamino]phenylpropionic acid, (R) 2-(4′-benzenesulfonylamino)phenylpropionic acid, (S) 2-(4′-benzenesulfonylamino)phenylpropionic acid, (R) 2-[4′-(2″-ethyl)benzenesulfonylamino]phenylpropionic acid, (S) 2-[4′-(2″-ethyl)benzenesulfonylamino]phenylpropionic acid, (R) 2-[4′-(2″-chloro)benzenesulfonylamino]phenylpropionic acid, (S) 2-[4′-(2″-chloro)benzenesulfonylamino]phenylpropionic acid, (R) 2-(4′-benzylsulfonylamino)phenylpropionic acid, (S) 2-(4′-benzylsulfonylamino)phenylpropionic acid, (R) 2-(4′-aminosulfonylamino)phenylpropionic acid, (S) 2-(4′-aminosulfonylamino)phenylpropionic acid, (R) 2-(4′-trifluoromethanesulfonylmethyl)phenylpropionic acid, (S) 2-(4′-trifluoromethanesulfonylmethyl)phenylpropionic acid, (R) 2-(4′-benzenesulfonylmethyl)phenylpropionic acid, and (S) 2-(4′-benzenesulfonylmethyl)phenylpropionic acid.
 4. The method according to claim 1, which comprises administering to a subject in need thereof an effective amount of a (R,S)-2-aryl-propionic acid compound of formula (Ia) or the single (R) or (S) enantiomer

or a pharmaceutically acceptable salt thereof, wherein Ar is a phenyl ring substituted in the 4 (para) position with a group selected from C₁-C₅-sulfonyloxy, substituted or not-substituted benzenesulfonyloxy, C₁-C₅-alkanesulfonylamino, substituted or not-substituted benzenesulfonylamino, C₁-C₅-alkanesulfonylmethyl, substituted or not-substituted benzenesulfonylmethyl.
 5. The method of claim 3, wherein said compound is in admixture with a suitable carrier thereof.
 6. A method for inhibiting IL-8 induced chemotaxis of human polymorphonucleated neutrophils and contemporaneously not inhibiting cyclooxygenase activity in a subject, which comprises administering to said subject in need thereof an effective amount of a (R,S)-2-aryl-propionic acid compound of formula (I) or the single (R) and (S) enantiomer

or a pharmaceutically acceptable salt thereof, wherein Ar is a phenyl ring substituted by: a group in the 3 (meta) position selected from a linear or branched C₁-C₅ alkyl, C₂-C₅-alkenyl or C₂-C₅-alkynyl group optionally substituted by C₁-C₅-alkoxycarbonyl, substituted or not-substituted phenyl, linear or branched C₁-C₅ hydroxyalkyl, aryl-hydroxymethyl, or a group in the 3 (meta) position selected from a linear or branched C₁-C₅ alkyl group, optionally substituted by C₁-C₅-alkoxycarbonyl, substituted or not-substituted phenyl, linear or branched C₁-C₅ hydroxyalkyl, aryl-hydroxymethyl, together with a substituent in the ortho or para position that comprises a benzene ring or a saturated or unsaturated, substituted or non-substituted bicycloaryl group; or a group in the 4 (para) position selected from C₁-C₅-acyloxy, substituted or not-substituted benzoyloxy, C₁-C₅-acylamino, substituted or not-substituted benzoylamino, C₁-C₅-sulfonyloxy, substituted or not-substituted benzenesulfonyloxy, C₁-C₅-alkanesulfonylamino, substituted or not-substituted benzenesulfonylamino, C₁-C₅-alkanesulfonylmethyl, substituted or not-substituted benzenesulfonylmethyl, C₃-C₆-cycloalkyl, 2-furyl, 3-tetrahydrofuryl, 2-thiophenyl, 2-tetrahydrothiophenyl, C₁-C₅ (alkanoyl)-C₁-C₅-alkylamino, C₁-C₈ (cycloalkanoyl)-C₁-C₅-alkylamino or C₁-C₈ (arylalkanoyl)-C₁-C₅-alkylamino; or a group in the 2 (ortho) position selected from substituted or not-substituted arylmethyl, substituted or not-substituted aryloxy, or substituted or not-substituted acylamino, wherein the substituents of the aryl group are selected from C₁-C₄ alkyl, C₁-C₄-alkoxy, chlorine, fluorine and/or trifluoromethyl groups, with the exception of (R,S)-2-(2′-benzylphenyl)-propionic acid.
 7. The method of claim 1, wherein the compound, enantiomer or pharmaceutically acceptable salt of the compound of formula (I) is one in which the Ar group is substituted at the 4 position by an acetyl-N-methyl-amino group or a pivaloyl-N-ethyl-amino group.
 8. The method of claim 2, wherein Ar is a phenyl ring 3-substituted by a 3-methyl-indan-5-yl group, 3-methyl-indan-7-yl group, 8-methyl-tetrahydronaphth-2-yl group or a 5-methyl-tetrahydronaphth-1-yl group.
 9. The method of claim 6, wherein the compound, enantiomer or pharmaceutically acceptable salt of the compound of formula (I) is one in which the Ar group is substituted at the 4 position by an acetyl-N-methyl-amino group or a pivaloyl-N-ethyl-amino group.
 10. The method of claim 6, wherein Ar is a phenyl ring 3-substituted by a 3-methyl-indan-5-yl group, 3-methyl-indan-7-yl group, 8-methyl-tetrahydronaphth-2-yl group or a 5-methyl-tetrahydronaphth-1-yl group. 